This application claims the benefit, under Title 35, United States Code, Section 119(a)-(d) and (f), of German Patent Application No. 198 27 417.3, filed on Jun. 19, 1998.
This application claims the benefit, under Title 35, United States Code, Section 365, of International Patent Application No. PCT/EP99/03778, filed on Jun. 1, 1999.
The invention relates to a material for differently modifying the optical properties of different cells, to an apparatus for the application of such a material, to a diagnostic apparatus for determining the optical properties of cells which have been exposed to such a material, and to an apparatus for irradiating cells whose optical properties have been differently modified with such a material.
Periodontosis is a widespread disease of the attachment apparatus of the teeth. Periodontopathies are caused by bacteria located in periodontal pockets (subgingivally). Some of these are bacteria which are bound adherently to the root surface and are usually Gram-positive and calcified to give concrements (subgingival calculus), and the others are bacteria which face the soft tissue of the pocket, are non-adherent and are usually Gram-negative, and which, for example, in part are motile in the pocket fluid. It is precisely these motile bacteria which play an essential role in the progression of periodontitis.
During the progression of periodontitis, the bacteria may migrate through the pocket""s epithelium and penetrate into the subepithelial connective tissue, so that they surround the inflammatory infiltrate. Complicated interactions occur with the patient""s immune defenses which are massively [lacuna] at this point and which lead, via (micronegroses, purulent abscesses or as reaction to the immune interaction for example through activation of osteoclastic endogenous cells, to loss of periodontal supporting tissue and development or deepening of a periodontal pocket and/or retraction of the gingival soft tissue. Particularly important in this connection are processes which take place deep inside the pocket or in problem regions such as, for example, the root furcation.
Recommended to date for reducing microbes in the pockets are mechanical cleaning techniques (for example scaling, curettages, cleaning with ultrasonic instruments) or simple pocket irrigations. Systemic administration of antibiotics is associated with considerable side effects, firstly because of the broad spectrum of the causative bacteria, and secondly because the bacteria are located outside the blood circulation. Local administration techniques through application of the antibiotics directly into the periodontal pockets often have an unreliable effect because diffusion into all the pocket regions is inadequate or deposition does not last long enough or the level of the active substance combination is inadequate. Antibiotics are therefore normally administered only as a measure supporting conventional, usually mechanical, procedures.
Because of the complex geometries of the affected periodontia or periodontal pockets, access to the diseased tissue regions is impeded, and the desired reduction in microbes is often not achieved. The consequence is after various time intervals, depending on the patient""s immunological predisposition which is usually affected, recolonization of a previously treated pocket with a recurrence of the disease. It is particularly difficult to reduce microbes in the region of the infiltrated pocket epithelium and the adjoining connective tissue.
The first requirement for improved therapy is to have more detailed information about the current status of the disease to allow a better prediction to be made about the future development of the disease, especially the occurrence of acute episodes of the disease. It is to date possible to identify a previously active pocket only subsequently on the basis of pus discharge from the pocket. If this identification is possible, however, loss of supporting tissue has already occurred. Bacterial genetic testing which has recently been employed for the diagnosis of individual bacteria in periodontal pockets is costly and requires several days for evaluation. For these reasons, it is unsuitable for routine applications. It is moreover possible to derive information only about the genomes of the bacteria from such testing. Distinction according to the metabolic activities of the bacteria which cause periodontal disease is, however, impossible.
Examples of a periodontal procedure are evident from U.S. Pat. Nos. 5,422,093; 5,234,940; 5,211,938 and 5,079,262. These involve the identification and subsequent treatment of malignant and nonmalignant tissue abnormalities using aminolevulinic acid. This is used in the form of an aqueous active substance solution. Excitation of cell fluorescence in the violet region (375 nm to 440 nm) leads to a red fluorescence being observed. An observation filter is used to filter out the diffusely reflected blue-violet excitation light, and the metabolically active tissue region is seen red against a background which appears slightly greenish (intrinsic fluorescence of the healthy tissue).
The rate constant with which metabolism takes place in the cells makes it necessary for the active substance to remain over a prolonged time (at least 15 minutes, typically 120 minutes) essentially unchanged in contact with the tissue.
The invention is therefore devoted to the problem of obtaining, in a simple manner at low cost and rapidly, information about the extent of a periodontitis, in particular also being able reliably to identify periodontitis in the initial stage.
To solve this problem, the invention indicates a material for differently modifying the optical properties of different cells (healthy tissue, diseased tissue, bacteria) which comprises firstly a substance which modifies the optical properties and secondly a basic material which is mechanically stable for a prolonged period under the conditions prevailing at the sites affected by periodontitis in a patient, and thus can release the modification substance over a prolonged period at the desired site. The proposed basic materials which are stable over a prolonged time under use conditions are viscous fluids, a gel, a two-dimensional or three-dimensional porous substrate or a material which hardens in situ (for example plastic film).
Materials which have different effects on different cells in a property typical of them are known in other medical sectors. Thus, for example, radioactive traces are used to identify cancer cells because they accumulate preferentially in the latter because of the greater metabolic turnover. Other modification substances are those which intervene directly in cell metabolism, stated more accurately in porphyrin biosynthesis. Administration of suitable modification substances, which are described in detail hereinafter, leads to intensification of the fluorescence spectrum of metabolically active cells. This makes it possible for these cells also to be determined quantitatively and in their spatial distribution, and the therapy can then be planned on the basis of this information.
It has now been realized that the technique developed in another medical sector for identifying diseased cells can also be employed in the periodontitis sector if the basic material used does not mix quickly with saliva and thus keeps the modification substance at the required site. Suitable for this purpose according to the invention are fluids having sufficient viscosity, gels, flat porous substrates such as wovens, nonwovens and the like or else three-dimensional porous substrates which are able to take up in their cavities particles of the modification substance or a concentrated solution thereof and thus release the modification substance distributed over a prolonged period. Another alternative consists of materials which harden in situ, such as film formers which bind or entrap the modification substance on the surface.
Advantageous further developments of the invention are indicated in dependent claims.
The further development of the invention ensures firstly that the basic material remains stable under the conditions acting on it at the site of use, and in addition does not change the surroundings to be investigated.
The further development of the invention permits easy application of the material but, nevertheless, ensures that the material is dimensionally stable to the required extent after application. The further development of the invention is also advantageous in relation to good dimensional stability of the material after application.
A material is particularly suitable for filling tooth pockets with negligible displacement of fluid from the tooth pockets. This makes it possible to diagnose the condition of a tooth pocket particularly well before the treatment.
The further development of the invention makes it possible to see at least through thin layers of the material, and for exciting light to be passed through the material.
Basic materials are suitable for in situ application of a material layer with particularly good dimensional stability.
On use of a material it is possible to use the time during which the material must remain at the site of use simultaneously for therapeutic purposes. Typical times between application of the material and the diagnosis of the cells modified by the material are about two hours. Thus a good therapeutic effect is also obtained in this waiting period.
The further development of the invention is advantageous in terms of good stability of the material in the oral environment, and such a material causes a negligible change in the initial condition of the cells or tissue regions to be investigated, also in terms of the pH.
Basic materials have been tested in the dental sector for a long time and are distinguished by excellent dimensional stability and good shape adaptation. Such a material serves well for investigations on tissue regions which are readily accessible.
The further developments of the invention permit diseased cells to be identified simply by eye or with use of a camera. It is possible in this way to establish easily with the eye or a camera the intensity of the disease and the spatial distribution of the diseased tissue regions. Such a direct optical image of the disease is particularly helpful for planning a therapy.
It is possible with a material easily to distinguish between cells which differ in metabolic activity but otherwise resemble one another greatly.
Influencing heme metabolism, is particularly informative and significant for a wide spectrum of different cells. The further development of the invention also has the advantage that such modification agents are available from the, other medical sectors (identification of cancerous tissues) mentioned at the outset. The corresponding substances can be synthesized at relatively reasonable cost.
The modification agent modifies the incorporation of iron into protoporphyrin, that is to say the last precursor of heme.
The invention specifies preferred concentrations of the modification substance which are advantageous in relation to pronounced modification on the one hand and not too great a change in the cell environment.
An apparatus facilitates the application of viscous or pasty material.
With an apparatus according to the invention it is possible with the application needle simultaneously to measure the depth of a tooth pocket and, when the depth of the tooth pocket is known, read off how far the needle has already been moved into the tooth pocket.
On use of an apparatus according to the invention the material is introduced into the tooth pocket gently so that the initial conditions are disturbed only slightly.
With an apparatus according to the invention it is possible to bring the material through the gingiva as far as tissue regions adjacent to the inner surface of the pocket.
The further development of the invention according to the invention is advantageous in relation to particularly delicate metering of material.
A diagnostic apparatus according to the invention makes it possible to inspect the cells which have been modified differently by the modification substance in a tooth pocket without the need to open the tooth pocket widely.
An apparatus according to the invention is able automatically to evaluate the proportions of healthy and diseased tissue and the intensity of bacterial invasion.
With an apparatus according to the invention the lateral dimension of the working head of the apparatus which can be introduced into the tooth pocket is particularly small. It can thus also be used for filming narrow periodontal pockets.
An apparatus according to the invention is able to measure simultaneously the root neck of a tooth and the inner surface of a periodontal pocket located next to the latter.
An apparatus according to the invention allows sequential surveying of individual strip regions of the tissue areas to be assessed and simultaneously ensures that the individual strip images can be automatically combined to give an overall two-dimensional image.
The achievement of the further development of the invention is to hold the photoconverters and the image converters at a distance from the lateral areas of a tooth pocket.
It is also known per se about the sector, mentioned at the outset, of the treatment of malignant and nonmalignant tissue abnormalities that the modification substances which are used therein and intervene in porphyrin metabolism bring about a photosensitization preferentially of the diseased cells. This photosensitization can be used to damage, by intensive beaming in of light of a suitable wavelength, these diseased cells so that they die. Such procedures are used in particular for the treatment of bladder carcinomas, brain tumors or carcinomas of the oral cavity.
The invention indicates an apparatus which utilizes for therapeutic purposes a photosensitization of diseased cells which has taken place in periodontal pockets.
On use of a flat light source for the therapy it is possible with an apparatus according to the invention to shield healthy tissue regions in the vicinity of a diseased tissue region from the therapeutic light and thus preclude damage to these regions.
The further development of the invention facilitates on the one hand the attachment of the mask parts and furthermore ensures that the mask parts also remain in the correct position during a prolonged treatment.
The choice of the wavelength of the therapeutic light according to the invention is advantageous in relation to maximally effective use thereof.
If it is wished to beam therapeutic light into a periodontal pocket through the open end of the latter, there is firstly the disadvantage that the periodontal pocket must be held open during the prolonged treatment, which causes pain, and secondly that the interior of the periodontal pocket is possibly not irradiated uniformly. The further development of the invention permits therapeutic light to be supplied two-dimensionally from the side through the gingiva. This eliminates the risk of shadows in the irradiation area.
With an apparatus according to the invention therapeutic light which is reflected from the tissue surface to be treated or from tissue located behind this is reflected a second time into the treatment zone. This results in a better yield of therapeutic light.
The achievement of the further development of the invention is that the therapeutic light reaches the site of administration with small scattering and refraction losses.
The further development of the invention is advantageous for larger irradiation areas because the therapeutic light is uniformly distributed.
The further development of the invention offers the advantage of a very high luminance for a short time but on average only slight thermal stress on the irradiated tissues.
The further development of the invention is advantageous in relation to protection of the applied modification material from interfering environmental effects.
An apparatus according to the invention can be used both as diagnostic apparatus and as therapeutic apparatus, it being necessary for changing over between these two modes of operation only to change the different filters placed in the light path between white light source and irradiation site.
The further development of the invention is advantageous in relation to effective feeding of light into a periodontal pocket. In this case it is unnecessary to open the periodontal pocket widely, and it is possible, by moving the light output element in a direction which is circular relative to the tooth axis (peripheral direction) also to carry out irradiations of different strengths according to a previously measured spatial distribution of the diseased cells, where appropriate at different sites of the root neck or the inner surface of the tooth pocket.
In this connection, the further development of the invention is advantageous when a larger irradiation area is desired with small dimensions of the light output element.
With the further development of the invention, refraction and scattering losses on inner boundary area which lie between the light output element and the area to be irradiated are kept small.